Abstract

Recent data indicate that alcohol dependence induces long-term neuroadaptations that recruit a negative emotional state. This leads to excessive alcohol ingestion motivated by relief of negative emotionality. A key mechanism in this transition to negative reinforcement is a recruitment of corticotropin-releasing factor (CRF) signaling within the amygdala. Long term upregulation of CRF(1) receptors is observed in the amygdala following a history of dependence, and CRF antagonists selectively block emotionality, excessive alcohol drinking and stress-induced reinstatement of alcohol-seeking in post-dependent animals. Innate upregulation of CRF(1) receptor expression mimics the post-dependent phenotype, both with regard to emotional responses and ethanol self-administration. Therefore, the CRF system is emerging as a key element of the neuroadaptive changes driving alcoholism and as a major target for its treatment.

The progression of alcohol dependence over time. The schematic illustrates the shift in underlying motivational mechanisms. From initial, positively reinforcing, pleasurable alcohol effects, the addictive process progresses over time to being maintained by negatively reinforcing relief from a negative emotional state. Data presented in this article suggest that neuroadaptations encompassing a recruitment of extrahypothalamic CRF systems are key to this shift.

Following a history of ethanol dependence induced by exposure to ethanol vapor, long-lasting neuroadaptations lead to the induction of excessive levels of voluntary alcohol consumption. (a) Post-dependent neuroadaptations can be induced by intermittently exposing animals to intoxicating alcohol levels over 7 weeks, and then allowing them to recover for 3 weeks to eliminate acute withdrawal. (b) A behavioral hallmark of the post-dependent phenotype is a marked and persistent upregulation of voluntary ethanol intake compared with animals that have been exposed to air only. Data taken from Ref. [].

A hallmark of all CRF1 receptor antagonists tested to date is their ability to block selectively excessive rates of operant alcohol self-administration, or excessive two-bottle free-choice alcohol consumption in post-dependent animals at doses that do not affect these behaviors in animals without a history of dependence [,]. This is illustrated here by the prototypical non-peptide CRF1 antagonist, R121919 (*P < 0.001 compared with the same drug dose in non-dependent animals; #P < 0.0001 compared with vehicle treatment in dependent animals). Clinical development of R121919 for major depression was discontinued, but similar data have been obtained with other non-peptide CRF1 antagonists that might have a potential for clinical development, such as antalarmin [,] or MTIP []. Redrawn, with permission, from Ref. [].

A long-term upregulation of the Crhr1 transcript, encoding the CRF1 receptor, is found within the amygdala complex in the post-dependent state, and is likely to mediate excessive alcohol consumption. (a,b) Illustrative sections of (a) control rats and (b) post-dependent animals that have been intermittently exposed to intoxicating alcohol levels over 7 weeks, and then allowed to recover for 3 weeks to eliminate acute withdrawal. (c) Quantitative analysis of in situ hybridization data from the two groups. Basolateral amygdala (BLA) and medial amygdala (MeA) are particularly affected. These data parallel, and provide a biological substrate for, observations that CRF1 receptor antagonists can block the elevated voluntary drinking and increased behavioral sensitivity to stress found in post-dependent animals. Data taken from Ref. [].